Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA.
Department of Nutrition Science, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Eur J Epidemiol. 2023 May;38(5):559-571. doi: 10.1007/s10654-023-00988-4. Epub 2023 Mar 25.
Modifiable factors can influence the risk for Alzheimer's disease (AD) and serve as targets for intervention; however, the biological mechanisms linking these factors to AD are unknown. This study aims to identify plasma metabolites associated with modifiable factors for AD, including MIND diet, physical activity, smoking, and caffeine intake, and test their association with AD endophenotypes to identify their potential roles in pathophysiological mechanisms. The association between each of the 757 plasma metabolites and four modifiable factors was tested in the wisconsin registry for Alzheimer's prevention cohort of initially cognitively unimpaired, asymptomatic middle-aged adults. After Bonferroni correction, the significant plasma metabolites were tested for association with each of the AD endophenotypes, including twelve cerebrospinal fluid (CSF) biomarkers, reflecting key pathophysiologies for AD, and four cognitive composite scores. Finally, causal mediation analyses were conducted to evaluate possible mediation effects. Analyses were performed using linear mixed-effects regression. A total of 27, 3, 23, and 24 metabolites were associated with MIND diet, physical activity, smoking, and caffeine intake, respectively. Potential mediation effects include beta-cryptoxanthin in the association between MIND diet and preclinical Alzheimer cognitive composite score, hippurate between MIND diet and immediate learning, glutamate between physical activity and CSF neurofilament light, and beta-cryptoxanthin between smoking and immediate learning. Our study identified several plasma metabolites that are associated with modifiable factors. These metabolites can be employed as biomarkers for tracking these factors, and they provide a potential biological pathway of how modifiable factors influence the human body and AD risk.
可改变的因素会影响阿尔茨海默病（AD）的风险，并可作为干预的目标；然而，将这些因素与 AD 联系起来的生物学机制尚不清楚。本研究旨在确定与 AD 的可改变因素（包括 MIND 饮食、体力活动、吸烟和咖啡因摄入）相关的血浆代谢物，并测试它们与 AD 表型的关联，以确定它们在病理生理机制中的潜在作用。在威斯康星州阿尔茨海默病预防队列的认知正常、无症状中年人群中，测试了 757 种血浆代谢物中的每一种与 4 种可改变因素之间的关联。在 Bonferroni 校正后，对具有显著意义的血浆代谢物进行了测试，以确定其与 AD 表型中的每一种（包括 12 种反映 AD 关键病理生理的脑脊液（CSF）生物标志物和 4 种认知综合评分）之间的关联。最后，进行了因果中介分析，以评估可能的中介效应。使用线性混合效应回归进行分析。共有 27、3、23 和 24 种代谢物分别与 MIND 饮食、体力活动、吸烟和咖啡因摄入相关。潜在的中介效应包括 MIND 饮食与临床前 AD 认知综合评分之间的β-隐黄质、MIND 饮食与即时学习之间的马尿酸、体力活动与 CSF 神经丝轻链之间的谷氨酸、吸烟与即时学习之间的β-隐黄质。我们的研究确定了几种与可改变因素相关的血浆代谢物。这些代谢物可以作为追踪这些因素的生物标志物，并且它们提供了一种潜在的生物学途径，说明可改变因素如何影响人体和 AD 风险。
